A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness

Beinborn, Martin; Worrall, Christine I.; McBride, Edward W.; Kopin, Alan S.

doi:10.1016/j.regpep.2005.05.001

Cited by 84 publications

(72 citation statements)

References 27 publications

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“…Replacing this residue with the neutral alanine or leucine greatly reduces affinity for GLP-1: however substitution with arginine has very little effect on receptor avidity indicating that a positive charge is required at this location for biological function (Al-Sabah and Donnelly, 2003). Finally, as stated above, the T149M mutation in the human GLP-1R is important in the biological activity of GLP-1 exhibiting both a reduced affinity for GLP-1 and a reduced cAMP activation (Beinborn et al, 2005).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 88%

“…One patient diagnosed with T2DM from a Japanese study (Tokuyama et al, 2004) exhibited impairment of insulin secretion, insulin sensitivity and glucose tolerance and had a missense mutation resulting in substitution of threonine 149 with methionine (T149M). The mutated receptor exhibited a reduced affinity in vitro for GLP-1 and Ex-4 (Beinborn et al, 2005).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

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Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

561

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Section: Glp-1r In the Pancreasmentioning

confidence: 88%

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

561

465

View full text Add to dashboard Cite

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“…The patient exhibited impaired glucose tolerance, insulin secretion and sensitivity. The mutated receptor had reduced affinity in vitro for GLP-1 and exendin-4 [209]. Further, GLP-1R mutants lacking Lys 334 -Leu 335 -Lys 336 of ICL3 in the HIT-T15 insulinoma cell line showed an absence of GLP-1 induced cAMP production, calcium channel activation and insulin secretion [245].…”

Section: Glp-1r Signal Transduction In Pancreatic β-Cellsmentioning

confidence: 97%

“…For example, a missense mutation of Thr 149 in TM1 reduced agonist binding [209]. Additionally, substitution of His 180 by arginine in TM2 resulted in a reduction in both the potency of cAMP production and affinity of the receptor for GLP-1 ( Figure 6) [200].…”

Section: Icls Ecls and Tm Domains Of The Glp-1rmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Thompson¹

2013

Clin Exp Pharmacol

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It has been estimated that approximately 8.4% of the world population currently live with diabetes mellitus and type 2 diabetes is the most common form. Type 2 diabetes increases the risk of complications such as heart attacks, blindness, amputations and kidney failure. Glucagon like Peptide-1 (GLP-1) is an effective insulinotropic agent and therefore its effects on insulin secretion have been greatly examined for more than two decades. It is a polypeptide hormone secreted by the intestinal L-cells into the blood in response to food uptake. GLP-1 has a very short half-life in vivo due to the rapid proteolytic degradation by Dipeptidyl Peptidase IV (DPP-IV). Therefore DPP-IV resistant GLP-1 analogues, Exenatide and Liraglutide, have been developed and are currently being used in the treatment of type 2 diabetes. GLP-1 agonist functions by binding to its receptor, GLP1R, on the cell surface.The GLP-1R belongs to the class B peptide receptor family based on its structure and function. The binding of GLP-1 to its receptor results in activation of Gαs coupled adenylyl cyclase and the production of cyclic Adenosine Monophosphate (cAMP), which enhances glucose-induced insulin secretion. Continuous GLP-1R activation also causes insulin secretion and pancreatic islet β-cell proliferation and neogenesis. The GLP-1R is internalised following its activation, which regulates the biological responsiveness of the receptor. Structurally the GLP-1R contains a large N-terminal extracellular domain (TM1-TM7) joined by three intracellular loops (ICL1, ICL2, ICL3) and three extracellular loops (ECL1, ECL2, ECL3), and an intracellular C-terminal domain. These domains play critical roles in GLP-1R trafficking to the cell surface, and also in agonist dependent activation and internalisation of the receptor. This review is focused on type 2 diabetes, its treatment with GLP-1, GLP-1R structure and function, and the physiological affects resulting from GLP-1R activation.

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“…A polymorphism in the GLP-1 receptor has been shown to alter response to GLP-1 in vitro [63]. To date, variation in GLP1R has not been associated with predisposition to type 2 diabetes.…”

Section: Genetic Predisposition To Disease Affecting Response To Pharmentioning

confidence: 99%

Pharmacogenetics: potential role in the treatment of diabetes and obesity

Vella

Camilleri

2008

Expert Opinion on Pharmacotherapy

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Background-Common genetic variation is associated with increased risk of common metabolic diseases such as type 1 and type 2 diabetes, and obesity. Increasing experience with genetic association studies has led to an understanding of the large sample sizes required to detect a weak to moderate genetic predisposition to disease, the need to reproduce such associations in independent cohorts, and the statistical criteria required to detect a true association. This approach has been used successfully to identify disease-associated gene variation usually in representative populations of large numbers.Objective-To review the current understanding of how common genetic variation influences predisposition to, and treatment of, metabolic disease. Methodology-Review of scientific literature.Results-While there has been progress in understanding how genetic variation predisposes to diabetes and obesity, and how candidate genes may alter drug response, several caveats limit the interpretation and significance of pharmacogenetic studies published to date: those caveats typically include relatively small numbers of participants and choice of endpoints in determining gene-associated differences in response, which may not be clinically significant or relevant as a biomarker or predictor of a desired clinical effect. The genetic variants studied at a given locus are often limited in number and may not represent a comprehensive map of the region under study.Conclusions-The pharmacogenetic associations in diabetes and obesity that have been reported to date have had limited impact on the choice of individual treatments. We perceive, however, that this field is in its infancy in these multifactorial metabolic diseases, and with further advances and future drug intervention trials designed in a way that allows a more clear interpretation of the impact of genetic variation on differences in drug response in obesity and diabetes, it is anticipated that pharmacogenetics will have a significant impact on individualizing medical care.

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A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness

Cited by 84 publications

References 27 publications

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Pharmacogenetics: potential role in the treatment of diabetes and obesity

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